Deregulation of the bone activity of an individual is the cause of many bone pathologies such as osteoporosis, Paget's disease or osteolytic tumors. Taking into account, in particular, the increase in human life expectancy, osteoporosis has become a public health problem and much research has been undertaken to remedy it. Since the bone pathologies under consideration are caused by an imbalance in bone remodeling to the benefit of the activity of osteoclasts, one of the routes of treatment envisioned consisted in reducing the activity of osteoclasts, in order to slow down the degradation of the bone material.
Bone is a composite of biopolymers, principally collagen, and an inorganic component identified as carbonate hydroxyapatite, approximated as (Ca,Mg,Na,M)10(PO4,CO3,HPO4)6(OH,CO2.
The concept and potential advantages of synthetic calcium phosphate materials as possible restorative material was first introduced at the beginning of the 20th century (Albee 1920, Ray and Ward 1951, Nery et Al., 1975). Apatitic or calcium phosphate cement (CPC) as a possible restorative material was first introduced by LeGeros et al. in 1982 and Brown & Chow in 1983.
There are presently a number of calcium phosphate materials on the market, in the form of powders, granules, mixtures with biocompatible polymers, implants, thin coatings or calcium phosphate cements (CPC).
The most widely used compounds are hydroxyapatite (HA, Ca10(PO4)6(OH)2) and tricalcium phosphate (TCP, Ca3(PO4)2). TCP has been shown to resorb rather quickly, but HA has advantages due to its chemical and physical properties similar to biological apatite crystals. A combination of TCP and HA, called biphasic calcium phosphate (BCP), provides a combination of these desirable properties (see Legeros R. et al. 2003).
Calcium phosphate bioceramics may be prepared by precipitation of powders from aqueous solutions of the starting chemicals. These powders are compacted under high pressure (between 100 and 500 MPa) and then sintered at a temperature between 1000° C. and 1300° C. (See Jarcho, 1986).
Biphasic calcium phosphate (BCP) may be obtained when calcium-deficient biologic or synthetic apatites are sintered at or above 700° C. An apatite is considered calcium deficient when the Ca/P ratio is less than the stoechiometric value of 1.67 for pure calcium hydroxyapatite.
Polymer-ceramic composites and polymer networks have been developed to provide suitable porosity, however generally at the expense of desirable mechanical properties (see Yang et al., 2001; Pompe W. et al. 2003).
To date, a wide variety of implant materials have been used to repair, restore, and augment bone. The most commonly used implants include autologous bone, synthetic polymers and inert metals. Protocols using these materials have significant disadvantages that can include patient pain, risk of infection during operations, lack of biocompatibility, cost, and the risk that the inserted hardware can further damage the bone. Therefore, a major goal of biomaterial scientists has been to develop novel bone substitutes that can be used as alternatives to these conventional techniques for skeletal repair.
Bone cements, such as cements based on polymethylmethacrylate (PMMA) offer certain advantages in avoiding the use of solid implants, but also have several disadvantages. Methacrylates and methacrylic acid are known irritants to living tissues, and when PMMA-based cements are cured in vivo, free radicals are generated, which can damage surrounding tissues. Moreover, the polymerization reaction for these materials is highly exothermic, and the heat evolved during curing can damage tissues. In addition, these materials are not biodegradable.
The concept and potential advantages of an apatitic or calcium phosphate cement (CPC) as a possible restorative material was first introduced by LeGeros et al in 1982 (“Apatitic Calcium Phosphates: Possible Restorative Materials”, J Dent Res 61(Spec Iss):343).
There are presently several CPC commercial products. CPC have the following advantage: malleability allowing them to adapt to the defect's site and shape. The introduction of injectable calcium phosphate cements greatly improved the handling and delivery of the cements and opened up areas of new applications for the CPC.
CPC systems consist of a powder and a liquid component. The powder component is usually made up of one or more calcium phosphate compounds with or without additional calcium salts. Other additives are included in small amounts to adjust setting times, increase injectability, reduce cohesion or swelling time, and/or introduce macroporosity.
Such materials are disclosed, for example, in EP 0 416 761, U.S. Pat. No. 4,880,610, U.S. Pat. No. 5,053,212, EP 0 664 133, EP 0 543 765, WO 96/36562 and WO 2004/000374.
The French patent application FR-2715853 describes compositions for biomaterials for resorption/substitution of support tissues, comprising a mineral phase composed of BCP or calcium-titanium-phosphate, and a liquid aqueous phase comprising an aqueous solution of a cellulose-based polymer. These injectable compositions contain no active principle.
Many studies have shown that gallium inhibits bone resorption and lowers plasma calcium through its antiresorptive activity (e.g., Warrell et al., 1984, 1985; Warrell and Bockman, 1989; Bernstein, L. R. 1998). For example, U.S. Pat. No. 4,529,593 discloses a method effective against excessive loss of calcium from bone using a gallium compound, such as gallium nitrate. The excessive loss of calcium may be linked to hypocalcaemia, osteoporosis or hyperparathyroidism. The gallium compound is administered intravenously, subcutaneously or intramuscularly.
Based on its antiresorptive activity, gallium has also been used in the clinical treatment of hypocalcaemia of malignancy (Warrell and Bockman, 1989) and Paget's disease of bone (Bockman and Bosco, 1994; Bockman et al., 1989, 1995). Gallium has also shown clinical efficiency in suppressing osteolysis and bone pain associated with multiple myeloma and bone metastases (Warrell et al., 1987, 1993), and has been suggested as a treatment for osteoporosis (Warrell, 1995). In vitro efficiency as antibacterial agent has also been reported (Valappil, 2008).
Gallium has long been known to concentrate in skeletal tissue, particularly regions of bone deposition and remodeling (e.g., Dudley and Maddox, 1949; Nelson et al., 1972). However, very little information exists on mechanisms of gallium uptake by bone cells and the mechanisms of skeletal gallium accumulation remain largely unknown. Gallium is known to adsorb in vitro to synthetic hydroxyapatite and as a result crystallization and probably dissolution of hydroxyapatite is decreased (Donnelly and Boskey, 1989; Blumenthal and Cosma, 1989). In a recent study, Korbas et al., 2004, reported experiments in which bone tissue incorporates in vitro gallium with a local structure similar to brushite. The gallium doped model compounds disclosed have a Ca/P molar ratio of 1 (ACP, brushite) and 1.66 (HAP).
Gallium nitrate is currently marketed as Ganite™, which product is administered through intravenous injection for the treatment of clearly symptomatic cancer-related hypocalcaemia that has not responded to adequate hydration. According to the FDA approved labelling for Ganite™, gallium nitrate exerts a hypocalcemic effect by inhibiting calcium resorption from bone, possibly by reducing increased bone turnover. Indeed, gallium may have an inhibitory effect on osteoclasts responsible for bone resorption and an increasing effect on osteoblasts responsible for bone growing without cytotoxic effect on bone cells (Donnelly, R., et al., 1993).
The incorporation of gallium into a biomaterial such as a calcium phosphate cement is not trivial. Indeed, the pH of an apatitic calcium phosphate cement paste is close to neutral, while the gallium ions are stable in solution only at pH<3 in form of an octahedral hexa-aqua complex or at pH>8 in form of gallate ions. This results in a quick and uncontrolled precipitation of amorphous Ga(OH)3 before complete setting of the cement. In addition, the gallium ions may interfere with the setting and hardening process, since gallium can trap phosphate ions resulting from the dissolution and precipitation process occurring during cement setting.